Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation

The eight catalytic subunits of the mammalian phosphoinositide-3-OH kinase (PI(3)K) family form the backbone of an evolutionarily conserved signalling pathway; however, the roles of most PI(3)K isoforms in organismal physiology and disease are unknown. To delineate the role of p110<img src="/__chars/alpha/black/med/base/glyph.gif" alt="alpha" align="bottom" border="0">, a ubiquitously expressed PI(3)K involved in tyrosine kinase and Ras signalling, here we generated mice carrying a knockin mutation (D933A) that abrogates p110<img src="/__chars/alpha/black/med/base/glyph.gif" alt="alpha" align="bottom" border="0"> kinase activity. Homozygosity for this kinase-dead p110<img src="/__chars/alpha/black/med/base/glyph.gif" alt="alpha" align="bottom" border="0"> led to embryonic lethality. Mice heterozygous for this mutation were viable and fertile, but displayed severely blunted signalling via insulin-receptor substrate (IRS) proteins, key mediators of insulin, insulin-like growth factor-1 and leptin action. Defective responsiveness to these hormones led to reduced somatic growth, hyperinsulinaemia, glucose intolerance, hyperphagia and increased adiposity in mice heterozygous for the D933A mutation. This signalling function of p110<img src="/__chars/alpha/black/med/base/glyph.gif" alt="alpha" align="bottom" border="0"> derives from its highly selective recruitment and activation to IRS signalling complexes compared to p110<img src="/__chars/beta/black/med/base/glyph.gif" alt="beta" align="middle" border="0">, the other broadly expressed PI(3)K isoform, which did not contribute to IRS-associated PI(3)K activity. p110<img src="/__chars/alpha/black/med/base/glyph.gif" alt="alpha" align="bottom" border="0"> was the principal IRS-associated PI(3)K in cancer cell lines. These findings demonstrate a critical role for p110<img src="/__chars/alpha/black/med/base/glyph.gif" alt="alpha" align="bottom" border="0"> in growth factor and metabolic signalling and also suggest an explanat